Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-08-26
1998-11-10
Richter, Johann
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
548150, 548151, 546198, 546199, 546133, 546138, 546112, 514305, 514299, 514321, 514322, A61K 31425, C07D41704
Patent
active
058344993
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/JP95/00385 filed Mar. 9, 1995 published as WO95/24399 Sep. 14, 1995.
1. Technical Field
The present invention relates to a 5-HT.sub.3 receptor agonist which comprises a thiazole derivative as an effective ingredient; and a novel thiazole derivative and a pharmaceutically acceptable salt thereof as well as an intermediate thereof.
2. Background Art
The compound of the present invention act as an effective and selective agonist for the neuronal serotonin (5-HT) receptor located in the primary afferent nerve of the enteric nervous system or central nervous system. This type of receptor is now considered as a 5-HT.sub.3 receptor. The compound of the present invention exerts its function by releasing acetylcholine from the efferent nerve ending in the digestive tracts. It is known that stimulation of the acetylcholine receptor in the digestive tracts accelerates motility of the gastrointestinal tracts and improves functional reduction of the gastrointestinal tracts (Goodman and Gilman's, The Pharmacological Basis of Therapeutics 8th edition, p. 125, (1990), Pergamon Press). It is also known that the 5-HT.sub.3 receptor is present in the presynaptic area of the central nervous system and inhibits nervous
In consequence, it is considered that a 5-HT.sub.3 receptor agonist is useful especially against gastrointestinal disorders.
Though no compound having a selective agonistic activity on the 5-HT.sub.3 receptor had been found, the inventors of the present invention reported that thiazole derivatives disclosed in WO 92/07849 possess a selective 5-HT.sub.3 receptor agonistic activity.
The compound having selective agonistic activities for the 5-HT.sub.3 receptor has not been found so far; however, the present inventors have reported that a thiazole derivative as disclosed in WO 92/07849 has selective agonistic activities for the 5-HT.sub.3 receptor.
The unexamined published Japanese patent application JP-A-62-252780 discloses a compound represented by the following formula: ##STR3## (refer to the above published application concerning the detailed definition). However, the compound disclosed in the above published application is substituted at the 2-position of indenothiazole by a substituent through a nitrogen atom, so that it is structurally different from the compound of the present invention. Moreover, in the published application, only antiulcer effects of the compound are disclosed and there is no disclosure about the selective agonistic activities for a 5-HT.sub.3 receptor.
The unexamined published Japanese patent application JP-A-5-51318 (WO 92/09586 pamphlet) describes, as an effective ingredient in the use claim, the compound represented by the following formula: ##STR4## (refer to the above published application concerning the detailed definition) and EP 0307141 describes, as an effective ingredient in the use claim, the compound represented by the following formula: ##STR5## (refer to the above document concerning the detailed definition), respectively. The compound (I), which will be described later, which is an effective ingredient for the pharmaceutical composition of the present invention, embraces the compounds described comprehensively in these documents. In these documents, however, there is only a description about the application of the compound for the preparation of an agent for suppressing active oxygen produced by neutrophils, that is, the preparation of a cholinergic neurosis drug and they do not include any description or suggestion that the compound has selective agonistic activities for 5-HT.sub.3 receptor.
DISCLOSURE OF THE INVENTION
The present inventors have proceeded with a further research on the agonistic activities for a 5-HT.sub.3 receptor under the technical circumstances as described above. The present inventors focused on an index for the 5-HT.sub.3 receptor agonistic activities, which is independent from the von Bezold-Jarisch reflex known as the index of Rev., 53, 159(1973)!, i.e., on the contractile effects of 5-HT on the isolated colon f
REFERENCES:
patent: 4952587 (1990-08-01), Baker et al.
patent: 5424431 (1995-06-01), Ohta et al.
Il Farmaco, vol. 50, No. 2, Feb. 1995, pp. 77-82, Perrone R. et al.: "Conformationally Restricted Thiazole Derivatives as Novel . . . Ligands".
Anan Hideki
Imanishi Naoki
Itahana Hirotsune
Ito Hiroyuki
Iwaoka Kiyoshi
Cross Lutz Laura
Richter Johann
Yamanouchi Pharmaceutical Co. Ltd.
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